Persistence of autoreactive myelin oligodendrocyte glycoprotein (MOG)‐specific T cell repertoires in MOG‐expressing mice

Abstract

Experimental autoimmune encephalomyelitis, an experimental murine model for multiple sclerosis, is induced by stimulation of myelin-specific T lymphocytes. Myelin oligodendrocyte glycoprotein (MOG), a minor component of myelin proteins, is a potent autoantigen which contributes extensively to the anti-myelin response. In the present work, immunoscope analyses and sequencing of the oligoclonal expansions revealed anti-MOG Va and Vb public repertoires in lymphocytes infiltrating the CNS of wild-type (WT) mice. Moreover, a subset of CNS-infiltrating CD4 + T lymphocytes bearing the public Vb8.2 segment have an inflammatory phenotype strongly suggesting that it is encephalitogenic. We then observed that, in lymph node cells of MOG-deficient and WT animals, the Va and Vb public repertoires expressed by MOG-specific T cells are identical in both strains of mice and correspond to those found in the CNS of WT animals. These findings indicate that the MOG immunodominant determinant is unable to induce tolerance by deletion, and public anti-MOG T cell repertoires are selected for, regardless of the presence of MOG in the thymus and peripheral organs. The generation of MOGKO mice has enabled researchers to probe the role of this autoantigen in shaping the autoimmune response [7]. Based on anti-MOG humoral and T cell responsiveness and encephalitogenic activity of MOG-primed T cells from these mice, we have previously found no evidence to support a gross tolerogenic effect of MOG expression. Nevertheless, only a complete picture of the autoreactive T cell repertoire can fully define the contribution of MOG to self tolerance.T cell repertoire studies have previously shown that immunodominant (ID) or subdominant peptide-specific T cells may express TCR with Va-Ja and/or Vb-Db-Jb rearrangements common to all mice or humans of the same MHC haplotype [8,9]. These recurrent rearrangements are referred to as public, while private ones were also observed, consisting of Va and Vb rearrangements that differ from one individual to another [8]. In a mouse model of tolerance to maternal Igj light chains, three public Vb-Jb rearrangements specific for a Cj peptide were found. These rearrangements are highly conserved and restored sequentially throughout life as tolerance vanished with the disappearance of Cj peptide presentation in lymphoid organs [10]. Moreover, in the B10.PL model of MBP-induced EAE, encephalitogenic T lymphocytes of Th1 phenotype express preferentially the public CDR3b, DAGGGY [11,12]. These works show that public rearrangements, found in all animals of the same MHC, can be used as molecular probes to monitor the presence of T lymphocytes specific for a well-defined epitope, and thereby provide evidence for the immunological status, tolerant or not, of the hosts. On the contrary, private repertoires cannot be used in the same way since they are expressed in one or few individuals only.Here we have precisely defined the encephalitogenic public TCR in MOG-induced EAE in WT mice. CNSinfiltrating CD4 + T cells expressing t...

T Cell Repertoire Diversity Is Required for Relapses in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis

“…A CDR3␤ of 10 aa with the GETGGNYAEQ sequence is found in all TdT Ϫ/Ϫ animals ( Table I, boldface letters), in agreement with the public CDR3␤ previously identified in C57BL/6 mice (25). In C57BL/6, eight different nucleotide sequences encode this public CDR3␤ among which seven contain N diversity (25). One sequence lacking N addition was found in both strains.…”

“…Wt and TdT Ϫ/Ϫ mice share the public CDR3␤ sequence GETGGNYAEQ (Ref. 25) and this work, suggesting a strong bias for this amino acid sequence encoded by eight different nucleotide sequences. Concerning the V␣-chain, the public V␣9-J␣23 rearrangement generating the CDR3␣ (RSYNQGKL) in wt mice is replaced in TdT Ϫ/Ϫ animals by CDR3␣ sharing the consensus sequence SxYNQGKL.…”

“…We have previously established that MOG 35-55-specific T lymphocytes express public rearrangements (25), i.e., common to all mice of the same MHC haplotype (26). These rearrangements, V␣9-J␣23, V␣9-J␣31, and V␤8.2-J␤2.1, have characteristic CDR3␣ and CDR3␤ sequences and are found in CNS-infiltrating cells during the disease and in MOG-stimulated lymph nodes cells (LNC) (25).…”

“…These rearrangements, V␣9-J␣23, V␣9-J␣31, and V␤8.2-J␤2.1, have characteristic CDR3␣ and CDR3␤ sequences and are found in CNS-infiltrating cells during the disease and in MOG-stimulated lymph nodes cells (LNC) (25). In the CNS, these public MOG-specific T cells have an inflammatory phenotype, i.e., secreting IFN-␥ and TNF-␣ (25).…”

“…We have previously determined that C57BL/6 mice express V␣ and V␤ public repertoires in response to the MOG 35-55 (25). We then analyzed the repertoire of TdT Ϫ/Ϫ MOG-specific T lymphocytes using the immunoscope method (29).…”